Plasma Meloxicam Concentrations Research Articles

PSII-3 Evaluation of a microneedle patch for the delivery of meloxicam in a veterinary application

Abstract In the livestock industry, animals undergo painful procedures such as castration and these practices have received increased scrutiny and concern regarding animal welfare. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat pain and inflammation in livestock. Novel administration routes such as transdermal drug delivery using polymeric biodegradable microneedle patches that are being developed to deliver drugs in a less stressful method. Therefore, the objective of this study was to evaluate meloxicam plasma concentrations when drug was delivered using a microneedle patch. Nursing pigs (n = 7; body weight = 3.69 ± 1.12 kg) from 1 litter were stratified into 1 of 3 treatment groups. Treatments were: 1) 0.5 mg of meloxicam/kg of body weight via oral drench (n = 2; oral); 2) a patch devoid of meloxicam (n = 1; placebo); or 3) 2.5 mg of meloxicam/kg of body weight delivered via microneedle patch (n = 4; patch). During the study, pigs remained in the crate with the sow and littermates. Blood was collected via jugular venipuncture for plasma analysis at 0, 8, 24, 48, and 72 h. An Estrotect Breeding Indicator strip was used to adhere the microneedle patch on the ear of the pigs. Briefly, the strip was cut to the size of the ear, a microneedle patch was placed at the center, and these were applied on the pinna of the ear after blood collection at 0 h. Statistical analyses were performed using the MIXED procedure of SAS 9.4 (Cary, NC) to assess the effects of treatment, time, and treatment × time interaction. Statistical significance was determined at P ≤ 0.05, with tendencies at 0.05 < P ≤ 0.1. There was a treatment × time interaction (P = 0.0074), with the pigs that received oral meloxicam having greater meloxicam plasma concentrations at 8 h compared with pigs that received a placebo patch or a patch containing meloxicam (P < 0.0001). There were no differences in plasma meloxicam concentrations between pigs receiving a placebo patch or a patch containing meloxicam (P = 0.9). Plasma levels of meloxicam were detectable but low in pigs that received a microneedle patch (0.91 ng/mL). Research is continuing to determine the ideal microneedle patch polymer and structure that would deliver meloxicam to achieve desired plasma concentrations.

PHARMACOKINETICS OF MELOXICAM AFTER SINGLE ORAL AND INTRAMUSCULAR ADMINISTRATION IN CHINA ROCKFISH (SEBASTES NEBULOSUS).

Fish species are important for various purposes including aquaculture stock and display animals, but there are significant gaps in the medical knowledge regarding pharmacological parameters and effective pain management. Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that has been studied in few teleost species and with several administration routes. However, these species were typically freshwater or euryhaline fish, and evaluation in marine species is lacking. The pharmacokinetic properties of meloxicam were determined in nine adult China rockfish (Sebastes nebulosus), presumed healthy based on physical examination and benign medical histories. Based on a pilot study, China rockfish were given 1 mg/kg meloxicam via IM injection in the epaxial musculature, and, after a 48-h washout period, 1 mg/kg meloxicam was given by PO gavage. Blood samples were collected from the caudal vein at baseline and at nine time intervals over a 48-h time period following administration of meloxicam. Plasma meloxicam concentrations were determined by reverse phase high-performance liquid chromatography, and noncompartmental analysis was performed. The mean peak plasma concentration after IM injection was 4.9 µg/ml, and the mean terminal half-life was 5.0 h. The mean peak plasma concentration after PO administration was 0.07 µg/ml. Based on these findings, IM injected meloxicam reaches plasma levels consistent with therapeutic concentrations in select mammals, and peak levels were maintained for ≤12 h. Single-dose PO administration failed to achieve similar concentrations, and clinical practicality is unknown. Further studies evaluating NSAID multidose regimes and their pharmacodynamic effects may provide additional dosing information.

Osmotic pump maintains plasma concentrations of meloxicam for 6 days after orthopedic surgery in pigeons (Columba livia).

To determine the plasma concentration of meloxicam delivered via an osmotic pump in pigeons undergoing orthopedic surgery and if an osmotic pump is a suitable alternative to repeated oral administration of this drug. 16 free-ranging pigeons presented for rehabilitation with a wing fracture. An osmotic pump filled with 0.2 mL of 40 mg/mL meloxicam injectable solution was implanted subcutaneously in the inguinal fold of 9 pigeons under anesthesia for orthopedic surgery. The pumps were removed 7 days postsurgery. Blood samples were collected before pump implantation (time 0) and 3, 24, 72, and 168 hours after pump implantation in 2 pigeons in a pilot study then at 12, 24, 72, and 144 hours in the 7 pigeons of the main study. The blood of 7 other pigeons receiving meloxicam at 2 mg/kg, PO, every 12 hours was also sampled between 2 to 6 hours after the last meloxicam administration. Plasma meloxicam concentrations were measured via high-performance liquid chromatography. The plasma concentration of meloxicam was maintained at significant levels from 12 hours to 6 days after osmotic pump implantation. Median and minimum plasma concentrations in implanted pigeons were maintained at the same or higher level than those measured in pigeons that received meloxicam at a dose known to be analgesic in this species. No adverse effects attributable to either osmotic pump implantation and removal or meloxicam delivery were observed in this study. Plasma concentrations levels of meloxicam in pigeons implanted with osmotic pumps were maintained at a similar concentration or higher than the suggested analgesic meloxicam plasma concentration in this species. Thus, osmotic pumps could represent a suitable alternative to the frequent capture and handling of birds for analgesic drug administration.

Pharmacokinetics of meloxicam in laying hens after single intravenous, oral, and intramuscular administration.

The objective of this study was to determine the pharmacokinetics of meloxicam after a single intravenous (IV), intramuscular (IM), and oral (PO) dose at 1mg/kg body weight in Jing Hong laying hens. Blood samples were collected at predetermined time points. Plasma meloxicam concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay method and then subjected to a non-compartmental analysis. After IV administration, meloxicam had a mean (±SD) volume of distribution at steady-state (Vdss ) of 206.50 ± 25.23 ml/kg, a terminal half-life (t1/2λ ) of 5.45 ± 0.53 h, and a total body clearance (Cl) of 26.48 ± 4.13 ml/h/kg. After PO and IM administration, meloxicam was absorbed relatively rapidly: the peak concentrations (Cmax s) of 3.04 ± 0.56 and 8.94 ± 2.31 μg/ml were observed at 3.08 and 0.80 h, respectively. After PO and IM administration, the absolute bioavailability (F) was determined as 70.13% and 125.50%, respectively. Assuming that hens shared the same analgesic threshold of meloxicam (0.5μg/ml) with humans, the plasma concentrations after three different routes (PO, IM, and IV) of administration were above this value for 16.7, 19.2, and 14.9h, respectively.

Pharmacokinetic Parameters and Estimating Extra-Label Tissue Withdrawal Intervals Using Three Approaches and Various Matrices for Domestic Laying Chickens Following Meloxicam Administration.

Meloxicam is commonly prescribed for treating chickens in backyard or small commercial operations despite a paucity of scientific data establishing tissue withdrawal interval recommendations following extra-label drug use (ELDU). Historically, ELDU withdrawal intervals (WDIs) following meloxicam administration to chickens have been based on the time when meloxicam concentrations fall below detectable concentrations in plasma and egg samples. To date, no studies have addressed tissue residues. ELDU WDIs are commonly calculated using terminal elimination half-lives derived from pharmacokinetic studies. This study estimated pharmacokinetic parameters for laying hens following meloxicam administration and compared ELDU WDIs calculated using tissue terminal elimination half-lives vs. those calculated using FDA tolerance and EMA's maximum regulatory limit statistical methods, respectively. In addition, ELDU WDIs were calculated using plasma meloxicam concentrations from live birds to determine if plasma data could be used as a proxy for estimating tissue WDIs. Healthy domestic hens were administered meloxicam at 1 mg/kg intravenous (IV) once, 1 mg/kg orally (PO) once daily for eight doses or 1 mg/kg PO twice daily for 20 doses. Analytical method validation was performed and meloxicam concentrations were quantified using high-performance liquid chromatography. In general, the terminal elimination technique resulted in the longest ELDU WDIs, followed by the FDA tolerance and then EMA's maximum residue limit methods. The longest ELDU WDIs were 72, 96, and 384 (or 120 excluding fat) h for the IV, PO once daily for eight doses, and PO twice daily for 20 doses, respectively. Plasma data are a possible dataset for estimating a baseline for tissue ELDU WDI estimations when tissue data are not available for chickens treated with meloxicam. Finally, pharmacokinetic parameters were similar in laying hens to those published for other avian species.

Pharmacokinetic Parameters and Tissue Withdrawal Intervals for Sheep Administered Multiple Oral Doses of Meloxicam.

Simple SummaryMeloxicam is an anti-inflammatory drug used to treat pain and inflammation in ruminants including sheep, and pharmacokinetic studies are needed to protect the food supply from drug residues after use in food-producing animals. This study estimated plasma pharmacokinetic parameters and meat withdrawal intervals (WDI) for market sheep after multiple daily oral doses of meloxicam. Single and multiple dose plasma pharmacokinetic studies, a multi-dose tissue depletion study, and a follow-up study to investigate if events prior to slaughter were associated with differences in plasma meloxicam concentrations, all using sample data collected after completion of dosing, were completed. Using regulatory agency methods for calculating withdrawal times, an estimated WDI of at least 10 d following the last dose is recommended for market lambs treated with ten daily oral 1 mg/kg doses of meloxicam tablets suspended in water. The effect of events surrounding slaughter on plasma meloxicam concentrations in lambs is unknown but should be considered if plasma samples are obtained immediately prior to or during the slaughter process and used for pharmacokinetic investigations.Meloxicam is an anti-inflammatory drug used to treat pain and inflammation in ruminants including sheep, and pharmacokinetic studies are needed to protect the food supply from drug residues after use in food-producing animals. This study estimated plasma pharmacokinetic parameters and meat withdrawal intervals (WDI) for market sheep after multiple daily oral doses of meloxicam. Single and multiple dose plasma pharmacokinetic studies, a multi-dose tissue depletion study, and a follow-up study to investigate if events prior to slaughter were associated with differences in plasma meloxicam concentrations, all using sample data collected after completion of dosing, were completed. Using regulatory agency methods for calculating withdrawal times, an estimated WDI of at least 10 d following the last dose is recommended for market lambs treated with 10 daily oral 1 mg/kg doses of meloxicam tablets suspended in water. The effect of events surrounding slaughter on plasma meloxicam concentrations in lambs is unknown but should be considered if plasma samples are obtained immediately prior to or during the slaughter process and used for pharmacokinetic investigations.

Preliminary bioequivalence of an oral integrating film formulation containing meloxicam with a suspension formulation in beagle dogs.

The oral disintegrating film (ODF) has advantages over suspension and tablet. These include convenience of administration, patient compliance, and accurate dosing. We evaluated the bioequivalence between the ODF and the meloxicam suspension by using a crossover design with a 3-week washout period. Six healthy male beagle dogs were randomized to receive both formulations of meloxicam, 2mg. Plasma meloxicam concentrations were measured at the same times. From the start until maximum concentration, the initial absorption of the ODF meloxicam formulation was more rapid (2.08±1.56hr) as compared to the suspension (3.33±1.03hr). Mean elimination half-lives were 28.77±4.01 and 32.85±9.79hr for the ODF and the suspension, respectively. Bioequivalence of the ODF was confirmed, based on the relative ratios of geometric mean concentrations (and 90% confidence intervals within the range of 80%-125%) for a maximum concentration of 101.05% (88.59-115.25), for the area under the plasma concentration-time curve (AUC) to the last sampling time of 96.07% (87.06-115.25), and for AUC to infinity of 92.65% (86.76-98.94). The meloxicam ODF may be used as an alternative to suspension formulations in the treatment of inflammatory joint diseases and painful musculoskeletal disorders.

Perioperative pharmacokinetics and pharmacodynamics of meloxicam in emus (Dromaius novaehollandiae) of different age groups using nonlinear mixed effect modelling.

Meloxicam is a widely used nonsteroidal anti-inflammatory drug in avian species. However, variability in pharmacokinetic (PK) and pharmacodynamic (PD) parameters in birds warrants species-specific studies for dose and dosing interval optimization. We performed a perioperative PK study of meloxicam (0.5mg/kg, intravenously) on emus of three different age groups: 3 chicks (5weeks old, 3.5kg), 4 juveniles (26weeks old, 18.8kg) and 6 adults (66weeks old, 38.8kg). A two-compartment population PK model including weight as a significant covariate on clearance and central volume of distribution (V1) best fitted the data. The typical values (20kg bird) for clearance and V1 were 0.54L/kg/h and 0.095L/kg. Both parameters significantly decreased with increasing weight/age. Meloxicam potency and selectivity for COX-1 and COX-2 were measured in whole blood assays (TxB2 production endpoint). Meloxicam was partially selective in emus (IC50 COX-1:COX-2=9.1:1). At the current empirical dose (0.5mg/kg/24hr), plasma meloxicam concentration is above IC50 of COX-2 for only 2hr. PK/PD predicted dose required for 80% COX-2 inhibition over 24hr were 3.4, 1.4 and 0.95L/kg/day in chicks, juveniles and adult emus, respectively. The safety, therapeutic efficacy and practicality of modifying the daily dose or dose interval should be considered for dose recommendations in emus.

Plasma pharmacokinetic profile and efficacy of meloxicam administered subcutaneously and intramuscularly to sheep.

Plasma pharmacokinetic profiles and the anti-inflammatory efficacy of meloxicam were determined when administered subcutaneously (SC) or intramuscularly (IM) to sheep. Merino ewes were initially injected with 0.1 mL of oil of turpentine into a forelimb to induce inflammation, followed by either 1.0 mg/kg or 2.0 mg/kg of meloxicam administered either SC or IM (n = 6 per treatment group) or followed by no meloxicam administration (control) (n = 4). Ewes were examined to determine skin temperature, limb circumference, limb sensitivity and signs of lameness at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 48 h following treatment, with blood collected at these time-points to quantify meloxicam plasma concentrations. Skin temperature of ewes dosed with meloxicam at 1.0 mg/kg SC and 2.0 mg/kg IM at 12 h and 1.0 mg/kg SC at 24 were significantly different to the controls (P < 0.05). Limb circumferences of ewes dosed with 1.0 mg/kg IM were significantly different to controls at 10 h and 12 h (P < 0.05). All meloxicam treatment groups resulted in reduced limb sensitivity compared to controls at 6 h, with the 1.0 and 2.0 mg/kg IM treatments significantly different at 12 h (P < 0.05) and 1.0 and 2.0 mg/kg SC groups, significantly different to controls at 48 h (P < 0.05). No significant difference in lameness scores were detected over 48 h. The 1.0 mg/kg IM treatment had a significantly greater plasma meloxicam concentration than the 1.0 mg/kg SC treatment over 0.5 to 4 h (P < 0.001). Both 1.0 mg/kg SC and IM treatments demonstrated elimination half-lives (mean ± SD) of 10.82 ± 2.46 and 12.63 ± 2.37 h, respectively. Meloxicam at all doses provided some anti-inflammatory and analgesic effects from 6 to 48 h; however no route could be distinguished as more efficacious than the others.

Pharmacokinetics of a Single Dose of Oral and Intramuscular Meloxicam in African Penguins ( Spheniscus demersus).

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that has been used orally and intramuscularly in numerous avian species, but not studied to date, in African penguins ( Spheniscus demersus). The study describes the pharmacokinetic parameters of meloxicam after oral and intramuscular administration to African penguins. Several pilot studies were conducted initially where meloxicam (1, 0.5, and 0.25 mg/kg) was given intramuscularly to 4 birds, and orally (1 mg/kg) to 2 birds. Based on pilot study results, one group of 8 penguins was given meloxicam 0.5 mg/kg intramuscularly and one group of 8 penguins was given 1 mg/kg orally. Blood samples were collected at baseline and at 11 time intervals per group after administration of meloxicam. Meloxicam time to maximum plasma concentration (Tmax), maximum concentration (Cmax), and half-life (t1/2) after intramuscular administration were 1.00 hour, 8.03 μg/mL, and 31.87 hours, respectively, while oral administration produced a Tmax, Cmax, and t1/2 of 12.00 hours, 10.84 μg/mL, and 28.59 hours, respectively. Based on plasma meloxicam concentrations found to be therapeutic in other bird species and humans, the recommended dosage and frequency for African penguins is 1 mg/kg orally every 48 hours and 0.5 mg/kg intramuscularly every 24 hours. Further studies are needed to determine the multiple-dose pharmacokinetics of meloxicam in African penguins.

Effect of oral administration of meloxicam prior to transport on inflammatory mediators and leukoctye function of cattle at feedlot arrival.

OBJECTIVE To investigate the effects of meloxicam administration before long-distance transport on inflammatory mediators and leukocyte function of cattle at feedlot arrival. ANIMALS 60 healthy yearling beef steers. PROCEDURES Single-source steers were assigned to a transported (n = 40) or nontransported (20) group. Then, half of the steers within each group were assigned to receive meloxicam (1 mg/kg, PO) or a lactose placebo (1 bolus/steer, PO). All steers were transported approximately 1,300 km overnight to a feedlot; however, the nontransported group was moved before treatment (meloxicam or placebo) administration and allowed a 17-day acclimation period, whereas the transported group was moved immediately after treatment administration on day -1. Blood samples for measurement of inflammatory mediators and leukocyte function were collected from all steers on days -1, 0, and 3. RESULTS For steers that received meloxicam, mean plasma meloxicam concentration for the transported group was significantly greater than that for the nontransported group on day 0. For steers that received the placebo, mean haptoglobin-matrix metalloproteinase-9 complex for the transported group was significantly greater than that for the nontransported group on day 0. Mean haptoglobin concentration, neutrophil L-selectin intensity, and polymorphonuclear leukocyte count for the transported group were significantly greater than those for the nontransported group. Mean substance P concentration for nontransported steers that received meloxicam was significantly lower than that for the other 3 treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated meloxicam administration to healthy steers immediately before long-distance transport did not significantly mitigate the effects of transport-induced stress on leukocyte function or inflammatory markers.

Pharmacokinetics of meloxicam after intramuscular and oral administration of a single dose to American flamingos (Phoenicopertus ruber).

OBJECTIVE To determine pharmacokinetics after IM and oral administration of a single dose of meloxicam to American flamingos (Phoenicopertus ruber). ANIMALS 14 adult flamingos. PROCEDURES Flamingos were allocated to 2 groups. Each group received a dose of meloxicam (1 mg/kg) by the IM or oral route. After a 4-week washout period, groups received meloxicam via the other route of administration. Plasma meloxicam concentrations were measured with high-performance liquid chromatography. Data for each bird were analyzed. Estimated values of selected pharmacokinetic parameters were compared by use of a linear mixed-effects ANOVA. Pooled concentration-time profiles for each route of administration were analyzed to examine the influence of body weight on pharmacokinetics. RESULTS Mean ± SD maximum plasma concentration was 1.00 ± 0.88 μg/mL after oral administration. This was approximately 15% of the mean maximum plasma concentration of 5.50 ± 2.86 μg/mL after IM administration. Mean time to maximum plasma concentration was 1.33 ± 1.32 hours after oral administration and 0.28 ± 0.17 hours after IM administration. Mean half-life of the terminal phase after oral administration (3.83 ± 2.64 hours) was approximately twice that after IM administration (1.83 ± 1.22 hours). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent and rate of meloxicam absorption were less after oral administration than after IM administration. Intramuscular administration resulted in a short period during which mean plasma concentrations met or exceeded reported efficacious analgesic concentrations in other species, whereas oral administration did not. These results suggested that higher doses may be required for oral administration.

PHARMACOKINETIC EVALUATION OF MELOXICAM AFTER INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION IN NILE TILAPIA (OREOCHROMIS NILOTICUS).

Critically evaluating the pharmacokinetic behavior of a drug in the body provides crucial information about how to effectively treat a patient. Pharmacokinetic studies that exist in fish have primarily focused on drugs used to treat infectious disease, with minimal attention given to analgesic drugs. The objective of this study was to determine the pharmacokinetics of meloxicam (1 mg/kg) in Nile tilapia ( Oreochromis niloticus ) (n = 12). A single dose of meloxicam was administered either i.v. or i.m. Blood samples were obtained at predetermined times after drug injection. Plasma meloxicam concentrations were determined by a validated liquid chromatography/mass spectrometry method, and noncompartmental pharmacokinetic analysis was performed. The mean peak plasma concentration after i.m. injection was 1.95 μg/ml. The mean terminal half-life of meloxicam after i.v. and i.m. administration was 1.36 and 1.8 hr, respectively. The area under the plasma concentration-versus-time curve extrapolated to infinity was 11.26 hr·μg/ml after i.v. administration and 5.72 hr·μg/ml after i.m. administration. Bioavailability of meloxicam after i.m. administration was approximately half that of i.v. administration. Elimination was rapid in both the i.m. and i.v. routes of administration, suggesting that maintaining clinically relevant plasma concentrations may be difficult using this dose. This study represents the first pharmacokinetic evaluation of a nonsteroidal anti-inflammatory drug in a fish species, and further studies evaluating efficacy are needed.

Pharmacokinetics of meloxicam in red-eared slider turtles (Trachemys scripta elegans) after single intravenous and intramuscular injections.

OBJECTIVE To determine the pharmacokinetics of meloxicam after single IV and IM injections in red-eared slider turtles (Trachemys scripta elegans). ANIMALS 8 healthy red-eared slider turtles. PROCEDURES Turtles received 1 dose of meloxicam (0.2 mg/kg) IV or IM (4 turtles/route), a 30-day washout period was provided, and then turtles received the same dose by the opposite route. Blood samples were collected at predetermined times for measurement of plasma meloxicam concentration. Pharmacokinetic values for each administration route were determined with a 2-compartment open model approach. RESULTS For IV administration, mean ± SD values of major pharmacokinetic variables were 1.02 ± 0.41 hours for distribution half-life, 9.78 ± 2.23 hours for elimination half-life, 215 ± 32 mL/kg for volume of distribution at steady state, 11.27 ± 1.44 μg•h/mL for area under the plasma concentration versus time curve, and 18.00 ± 2.32 mL/h/kg for total body clearance. For IM administration, mean values were 0.35 ± 0.06 hours for absorption half-life, 0.72 ± 0.06 μg/mL for peak plasma concentration, 1.5 ± 0.0 hours for time to peak concentration, 3.73 ± 2.41 hours for distribution half-life, 13.53 ± 1.95 hours for elimination half-life, 11.33 ± 0.92 μg•h/mL for area under the plasma concentration versus time curve, and 101 ± 6% for bioavailability. No adverse reactions were detected. CONCLUSIONS AND CLINICAL RELEVANCE Long half-life, high bioavailability, and lack of immediate adverse reactions of meloxicam administered IM at 0.2 mg/kg suggested the possibility of safe and effective clinical use in turtles. Additional studies are needed to establish appropriate administration frequency and clinical efficacy.

Pharmacokinetics of a Single Dose of Oral and Subcutaneous Meloxicam in Caribbean Flamingos ( Phoenicopterus ruber ruber).

To determine the pharmacokinetics of meloxicam in Caribbean flamingos ( Phoenicopterus ruber ruber), a pilot study was performed first, followed by a complete pharmacokinetic study. Four healthy birds were divided into 2 groups and administered 1 mg/kg of either oral (n = 2) or subcutaneous (n = 2) meloxicam. Plasma meloxicam concentrations were determined with liquid chromatography-mass spectrometry. Based on the pilot study results, 12 healthy birds were assigned into 2 groups and administered either 3 mg/kg PO (n = 6) or 1.5 mg/kg SC (n = 6) of meloxicam. Blood samples were collected at baseline and at 9 time intervals per group after administration of meloxicam in all flamingos. Plasma concentrations after administration of 3 mg/kg PO meloxicam reached a mean maximum plasma concentration of 1.449 μg/mL at 2.35 hours with a terminal half-life of 1.832 hours. After administration of 1.5 mg/kg SC meloxicam, maximum plasma concentration was 4.059 μg/mL at 0.91 hour with a terminal half-life of 1.104 hours. The plasma profile from the main oral study (3 mg/kg PO) differed markedly from the pilot study (1 mg/kg PO), suggesting a delayed absorption with the higher dose and lack of dose proportionality. The different doses for subcutaneous administration resulted in a proportional change in plasma concentrations. Further studies are needed to evaluate the effects of the drug volume administered and fasting status when oral dosing is used. Future studies are also needed to investigate multiple-dose pharmacokinetics of meloxicam and to determine the therapeutic meloxicam plasma concentration in Caribbean flamingos.

Pharmacokinetics and tissue disposition of meloxicam in beef calves after repeated oral administration.

The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British×Continental beef calves aged 4 to 6months and weighing 297-392kg received 0.5mg/kg meloxicam per os once daily for 4days. Plasma meloxicam concentrations were determined in 8 calves over 6days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n=3/timepoint), and 19days (n=4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025μg/mL) and muscle, liver, kidney, and fat samples (LOQ=2ng/g) after extraction using validated LC-MS-MS methods. The mean (± SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52±0.87μg/mL, 2.95±0.77 μg/mL, and 3.84±0.81μg/mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67±118.16ng/g) and kidney samples (52.73±39.01ng/g) at 5days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21days after repeated oral administration.

Pharmacokinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days

To determine the pharmacokinetics and safety of meloxicam in rabbits when administered orally for 29 days. 6 healthy rabbits. Meloxicam (1.0 mg/kg, PO, q 24 h) was administered to rabbits for 29 days. Blood was collected immediately before (time 0) and 2, 4, 6, 8, and 24 hours after drug administration on days 1, 8, 15, 22, and 29 to evaluate the pharmacokinetics of meloxicam. On day 30, an additional sample was collected 36 hours after treatment. Plasma meloxicam concentrations were quantified with liquid chromatography-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. Weekly plasma biochemical analyses were performed to evaluate any adverse physiologic effects. Rabbits were euthanatized for necropsy on day 31. Mean ± SD peak plasma concentrations of meloxicam after administration of doses 1, 8, 15, 22, and 29 were 0.67 ± 0.19 μg/mL, 0.81 ± 0.21 μg/mL, 1.00 ± 0.31 μg/mL, 1.00 ± 0.29 μg/mL, and 1.07 ± 0.19 μg/mL, respectively; these concentrations did not differ significantly among doses 8 through 29. Results of plasma biochemical analyses were within reference ranges at all time points evaluated. Gross necropsy and histologic examination of tissues revealed no clinically relevant findings. Plasma concentrations of meloxicam for rabbits in the present study were similar to those previously reported in rabbits that received 1. 0 mg of meloxicam/kg, PO every 24 hours, for 5 days. Results suggested that a dosage of 1. 0 mg/kg, PO, every 24 hours for up to 29 days may be safe for use in healthy rabbits.

Meloxicam pharmacokinetics using nonlinear mixed‐effects modeling in ferrets after single subcutaneous administration

This study was designed to investigate the pharmacokinetics of meloxicam, an oxicam class, nonsteroidal anti-inflammatory drug (NSAID), in ferrets. We determined the pharmacokinetic properties of a single subcutaneous dose of meloxicam (0.2 mg/kg) in nine male and nine female ferrets. Blood samples were collected by venipuncture of the cranial vena cava into heparinized syringes. Plasma meloxicam concentrations were determined by high-pressure liquid chromatography (HPLC). Pharmacokinetic variables were calculated using nonlinear mixed-effects modeling to take advantage of the population-based sampling scheme and to minimize sample volume collected per animal. Maximum plasma concentration, volume of distribution per absorption, and elimination half-life were 0.663 μg/mL, 0.21 L, and 11.4 h, respectively, for females and 0.920 μg/mL, 0.35 L, and 17.8 h, respectively, for males. Significant differences were found in each of the above parameters between male and female ferrets. Systemic clearance per absorption was not affected by gender and was 13.4 mL/h. Analgesic efficacy was not evaluated, but plasma meloxicam concentrations achieved in these animals are considered effective in other species. Sex differences in the pharmacokinetic behavior of meloxicam should be taken into consideration when treating ferrets.

Impact of oral meloxicam administered alone or in combination with gabapentin on experimentally induced lameness in beef calves1

This study examined the pharmacokinetics and analgesic effect of oral meloxicam (MEL) administered alone or in combination with gabapentin (GABA) in an experimental bovine lameness model. Eighteen male British × Continental beef calves aged 4 to 6 mo and weighing 297 to 392 kg were randomly assigned to receive either 1) 0.5 mg/kg lactose monohydrate placebo (PLBO; n = 6), 2) 0.5 mg/kg MEL (n = 6), or 3) 0.5 mg/kg MEL combined with 15 mg/kg GABA (MEL-GABA; n = 6) once daily for 4 d. The first treatment was administered 4 h after a chemical synovitis/arthritis was induced with injection of 15 mg amphotericin B into the left hind lateral distal interphalangeal joint. Changes in activity were evaluated continuously with pedometers. Contact force, contact area, contact pressure, impulse, and stride length were recorded once daily with a pressure mat and visual lameness scores were determined by a masked observer using a 5-point scale. Cortisol and drug concentrations were determined daily by immunoassay and HPLC-mass spectrometry, respectively. Outcomes were compared statistically using a random effects mixed model and analysis of covariance. There was a positive association between lameness scores and serum cortisol concentrations (P = 0.02) and a negative association between lameness score and step count (P < 0.0001), total force (P = 0.001), force applied to the lateral claw (P = 0.02), contact pressure (P = 0.005), and impulse of the lateral claw (P = 0.01). Step count was greater in MEL calves compared with PLBO (P = 0.008) and MEL-GABA (P = 0.04) calves. Impulse was greater in the MEL-GABA calves compared with the PLBO calves (P = 0.03). There was an inverse relationship between plasma MEL concentrations and lameness score (P = 0.02) and a positive association between MEL concentrations and force applied to the lateral claw (P = 0.03), total contact pressure (P = 0.03), and impulse on the lateral claw (P = 0.02). There was a tendency towards a positive association between GABA concentrations, total impulse, and impulse on the lateral claw (P = 0.08) and a negative associate between GABA concentrations and step count (P = 0.08). The results of this study suggest that MEL administered alone or in combination with GABA reduced the severity of lameness in calves following induction of lameness with amphotericin B. These findings have implications for developing analgesic protocols in lame calves that address both production and welfare concerns.

Impact of oral meloxicam on circulating physiological biomarkers of stress and inflammation in beef steers after long-distance transportation1

Transportation stress can result in significant economic losses to producers due to decreased animal productivity and increased medication costs associated with sickness such as bovine respiratory disease (BRD). Meloxicam (MEL) provides pain relief and anti-inflammatory effects in cattle for several days after a single oral treatment. Our hypothesis was that MEL administration before shipping would reduce the impact of long-distance transportation on circulating physiological biomarkers of stress and inflammation in beef steers. Ninety-seven beef steers were blood sampled for baseline biomarker determination and then randomly assigned to receive either 1 mg/kg MEL (n = 49) or a placebo (CONT; n = 48) per os before a 1,316-km transportation event lasting approximately 16 h. Calves were then blood sampled on arrival and 5 d later. Changes in the hemogram, circulating plasma proteins, total carbon dioxide (TCO2), fibrinogen, substance P (SP), cortisol, haptoglobin (Hp)-matrix metalloproteinase-9 (MMP-9) complexes, and tumor necrosis factor α (TNFα) between treatments over time were compared using a mixed effects model with statistical significance designated as P < 0.05. Analysis of covariance was conducted to assess the relationship between circulating MEL concentrations and biomarker changes over time. An increase in neutrophil, platelet, monocyte, white blood cell, and red blood cell counts occurred after transportation (P < 0.0001) and a decrease in lymphocyte count were observed (P < 0.0001). Meloxicam treatment reduced the stress-induced neutrophilia (P = 0.0072) and circulating monocyte count (P = 0.013) on arrival. Mean corpuscle hemoglobin (P = 0.05), mean corpuscle volume (P = 0.05), and lymphocyte count (P = 0.05) were also greater in the CONT calves compared with MEL calves after transportation. Furthermore, Hp-MMP-9 complexes, TCO2, TNFα, plasma proteins, and SP increased and cortisol decreased after shipping (P < 0.01). Meloxicam treatment tended to reduce serum cortisol concentrations (P = 0.08) and there was evidence of a time × treatment interaction (P = 0.04). An inverse relationship between plasma MEL concentrations and circulation cortisol concentrations (P = 0.002) and neutrophil (P = 0.04) and basophil counts (P = 0.03) was also observed. The results suggest that MEL administration may reduce the impact of long-distance transportation on circulating physiological biomarkers of stress and inflammation in beef calves.